A devastating mutation occurs in a gene involved in the processing steps of glyc
ID: 257010 • Letter: A
Question
A devastating mutation occurs in a gene involved in the processing steps of glycosylation within the Golgi. The particular gene is involved in the building of mannose-6-phosphate glycosylations. With the mutation, the golgi can no longer build mannose-6-phosphate glycosylations. a. What is the function of proteins that receive the mannose-6-phosphate residues on them? (2) b. Where do proteins that receive mannose-6-phosphate normally end up in the cell? (2 pts) b. What process (or processes) might not function properly now that these proteins do not have the correct glycosylation? (3 pts)
Explanation / Answer
A).
The mannose 6-phosphate receptors (MPRs) are transmembrane glycoproteins target enzymes to lysosomes in vertebrates.
Mannose 6-phosphate receptors bind newly synthesized lysosomal hydrolases in the trans-Golgi network (TGN) and deliver them to pre-lysosomal compartments. There are two different MPRs, one of ~300kDa and a smaller, dimeric receptor of ~46kDa.
The larger receptor is known as the cation-independent mannose 6-phosphate receptor (CI-MPR), while the smaller receptor (CD-MPR) requires divalent cations to efficiently recognize lysosomal hydrolases. While divalent cations are not essential for ligand binding by the human CD-MPR, the nomenclature has been retained.
B).
We now consider the pathway that delivers lysosomal hydrolases and membrane proteins to lysosomes. Both classes of proteins are synthesized in the rough ER and transported through the Golgi apparatus to the trans Golgi network.
The transport vesicles that deliver these proteins to late endosomes (which later form lysosomes) bud from the trans Golgi network. The vesicles incorporate the lysosomal proteins and exclude the many other proteins being packaged into different transport vesicles for delivery elsewhere.
C).
A phosphatase within late endosomes generally removes the phosphate from lysosomal enzymes, preventing their rebinding to the M6P receptor.
The lysosomal enzymes we have talked about so far are actually precursors, or proenzymes. These catalytically inactive proenzymes are the ones sorted by the M6P receptor. Late in its maturation a proenzyme undergoes a proteolytic cleavage that causes a conformational change in the protein, forming a smaller but enzymatically active polypeptide.
This cleavage occurs in either the acidic late endosome or the lysosome. Delaying the activation of lysosomal proenzymes until they reach the lysosome prevents them from digesting macromolecules in earlier compartments of the secretory pathway.